Bidirectional relationship between SARS-CoV-2 and Diabetes Mellitus

Several studies demonstrated that COVID-19 has a more severe outcome in patients with diabetes; in addition, in normoglycemic patients, the infection can alter glycometabolic control increasing the risk to develop Type 2 Diabetes (T2D) or dysglycaemia. Thus, a bidirectional relationship between COVID-19 and diabetes can be hypothesized but a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2) is a necessary step for SARS-CoV-2 infection permissiveness. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyze ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies. Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing β-cells. ACE2 is also highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. Moreover, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, increase ACE2 expression in the β-cell line EndoC-βH1 and in primary human pancreatic islets. Finally, we demonstrated that ACE2 expression is increased in pancreatic islets of T2D donors in comparison to non-diabetic controls alongside with a higher colocalization rate between ACE2 and insulin using both anti-ACE2 antibodies. Of note, a higher frequency of peri-islets macrophages was detected in T2D donors respect to non-diabetic. Upregulation of ACE2 was demonstrated in pancreatic islet β-cells of T2D donors. Higher ACE2 expression in T2D islets might increase their susceptibility to SARS-CoV-2 infection during COVID-19 disease in T2D patients, thus exacerbating glycometabolic outcomes and worsening the severity of the disease. Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes.